This career development award proposal (Treatment of Opiate Dependence through Inhibitors of Fatty Acid Amide Hydrolase) builds upon previous training of the candidate, in the area of the behavioral effects of enhancing endocannabinoid tone via inhibition of their degradative enzymes, and in the area of models of opioid self-administration and dependence. The aim of this proposal is to examine and follow up on data produced by the candidate that suggests that chronic inhibition of fatty acid amide hydrolase (FAAH), the primary enzyme responsible for degrading the endocannabinoid anandamide, blunts the progression of dependence in a heroin self-administration model while also blunting increases in the serum levels of the stress hormone corticosterone. To effectively determine the mechanisms and neurobiology underlying these phenomena will require training to examine the reward state of the animals, during the progression of heroin use, using intracranial self-stimulation. In addition, learning biochemical techniques required toward effectively characterizing the neurological changes occurring due to heroin abuse, and that which is reversed by FAAH inhibition, will allow a greater understanding of the brain regions and adaptations critical to preventing the progression of heroin dependence. Biochemical measures that will be employed will include: gene expression, protein quantification, enzyme activity, and endocannabinoid quantification. Under the tutelage of Dr. Benjamin Cravatt, an expert in the area of biochemical measure of endocannabinoid activity, along with the expertise in drug-abuse related behavioral models provided through the support of Dr. George Koob, the candidate will be able to integrate converging lines of evidence to demonstrate the roles that reward and stress play in the utility of the endocannabinoid system against opioid addiction. The Scripps Research Institute environment will also be utilized to provide training that will enhance the readiness of the candidate for a career as an independent investigator, including specialized courses in effective lab management and proper research conduct. The project will focus on the mechanisms by which FAAH inhibition are, or could potentially be, therapeutically advantageous in the treatment of opioid dependence. Changes in reward thresholds, which are established to increase with heroin use, are hypothesized to be normalized in the presence of FAAH inhibitor treatment. Furthermore, biochemical changes associated with negative affective-like states during drug withdrawal, exemplified by changes in CRF and glucocorticoid receptor expression, will be examined in the presence and absence of treatment with FAAH inhibitors. These biochemical changes will then be corroborated by heroin withdrawal-induced measures of anxiety- and depressive-like behaviors. Finally, the generation of a genetically-targeted FAAH-deficient rat will allow the examination of changes in stress-related genes due to protracted heroin withdrawal, and long-term FAAH inactivation on the relapse susceptibility to heroin in the presence of drug, cues, and stressors. Combined, the project will further the science on the understanding on heroin addiction, drug addiction as a form of repeated stress, the role of endocannabinoids to break the cycle of drug abuse through the reduction of drug-associated stressors and anhedonia.